The main goal of this research is to test a novel approach for preventing estrogen receptor (ER) -negative breast cancer. Of the approximately 40,000 deaths predicted to occur in 2003 due to breast cancer, 12-15,000 will be ER-negative, and of the anticipated 213,000 new breast cancer cases, one third will be ER-negative. While antiestrogenic approaches offer considerable promise for preventing ER-expressing breast cancers, new approaches are required to prevent or treat ER-negative breast cancers. Two drug classes currently under investigation as chemopreventive agents are those targeting cyclooxygenase (COX) enzymes and retinoid receptors. In particular, isoform-specific agents, namely selective COX-2 inhibitors and retinoid X receptor (RXR) ligands, appear to be effective chemopreventives with reduced toxicity relative to non-selective compounds. COX-2 is strongly implicated in tumorigenesis: COX-2 deficiency protects against intestinal and skin tumor formation in experimental animals, and, conversely, mammary-targeted COX-2 overexpression causes breast cancer in mice. Importantly, COX-2 is expressed in approximately 40% of human breast cancers, particularly in those which are ER-negative. COX-2 positivity also correlates with HER2/neu overexpression, which occurs in 20-30% of human breast cancers. We have shown that the selective COX-2 inhibitor celecoxib protects against the formation of experimental ER-negative breast cancer in MMTV/neu mice. The RXR-selective retinoid LGD1069 also delays tumor onset in this model. However, neither agent alone is sufficient to totally prevent tumor formation. The hypothesis underlying the proposed study is that the combination of a selective COX-2 inhibitor with an RXR-selective retinoid will be more effective than either agent alone for preventing ER-negative breast cancer. To test this hypothesis, tumor incidence will be compared in MMTV/neu mice administered both celecoxib and LGD1069, with those receiving either agent alone, and with control animals. Additionally, tumor growth rates following initial detection will be compared in control and drug-treated animals to determine if tumor growth is decreased by drug treatment. Biological endpoint assays will be performed to investigate the mechanistic basis of observed anticancer effects, including assays of proliferation, apoptosis, and angiogenesis. The results of this study will provide the basis for evaluating this combination approach in women at high risk for breast cancer.